Immunotherapy and Overall Survival Among Patients With Advanced Non–Small Cell Lung Cancer and Obesity

Key Points Question For patients with advanced non–small cell lung cancer (aNSCLC) and obesity who potentially have an inadequate therapeutic response to anti–programmed cell death 1 therapy, is conventional chemotherapy or immune checkpoint inhibitor the optimal choice as first-line therapy? Findings In this cohort study, 31 257 patients with aNSCLC were identified. Immune checkpoint inhibitor was not associated with improved survival compared with conventional chemotherapy in patients with aNSCLC and overweight or obesity. Meaning The findings of this study suggest that immune checkpoint inhibitor therapy may not be the optimal first-line therapy in patients with overweight or obesity and aNSCLC; hence, the use of conventional chemotherapy should also be considered in such patients.


Subgroups analyses by age category and sex
To account for the potential influence of age and sex on the relationship between BMI and mortality, the main analyses were repeated within subgroups of patients categorized by age (≤ 64 years, 65-79 years, and ≥ 80 years) and sex (male and female).

Sensitivity analysis 1 on length of period before lung cancer
Two sensitivity analyses were conducted to examine the robustness of the main results by changing the following definitions.We included those with a minimum 3-month interval from database entry to the date of first lung cancer diagnosis (sensitivity analysis 1).

Sensitivity analysis 2 with censoring at time of regimen cross-over
As a sensitivity analysis 2, we also conducted a method of "Excluding cross-overs" in which we excluded patients who switched over their regimens during a follow-up period.This sensitivity analysis included patients who received ICI monotherapy and conventional chemotherapy.If a patient receiving ICI monotherapy, started conventional chemotherapy, he or she was excluded from the analysis.Similarly, if a © 2024 Ihara Y et al.JAMA Network Open.
patient receiving conventional chemotherapy, started ICI therapy, he or she was excluded from the analysis.
Sensitivity analysis 3 in missing value completion of BMI 4,696 patients were excluded from the analysis due to missing BMI information.Missing data on BMI were caused by participating hospitals' decision on providing or not providing BMI information to MDV.Patients' baseline characteristics among patients with missing BMI were compared between ICI and conventional chemotherapy groups (Appendix eTable 6).The distributions of all baseline characteristics appeared to be similar between the two cohorts.We also have added a sensitivity analysis using multiple imputation methods.Multiple imputation with predictive mean matching was used to address missing values of BMI in addition to Barthel index score and smoking status, and analysis was performed on the imputed dataset (sensitivity analysis 3).

Additional analysis
As an additional analysis, ICI therapy was further divided into chemoimmunotherapy combination (combination therapy of ICI and conventional chemotherapy) and ICI monotherapy (including in nivolumab + ipilimumab).The estimated hazard function of mortality was plotted on a log scale against continuous BMI values.eFigure 2 shows the log of the mortality hazard as a function of BMI, stratified by therapeutic type in sensitivity analysis 1, sensitivity analysis 2 and sensitivity analysis 3 populations.A consistent trend was associated with a lower hazard of mortality for patients with a higher BMI in both therapy types for all sensitivity analyses (eFigure 2A, 2C, 2E).However, in sensitivity analysis 2, the mortality hazard was higher for patients with higher BMI.The association of lower mortality in patients treated with ICI compared with those treated with conventional chemotherapy was observed to disappear before and after overweight or obesity in all sensitivity analyses (eFigure2B, 2D, 2F).

eMethods 1 .
Definitions of Patients With NSCLC Who Received First-Line Therapy eMethods 2. Patient Exclusion Criteria eMethods 3. Definitions of Patient Demographic and Clinical Characteristics eMethods 4. Detailed Information on Each Analysis eTable 1. ATC Codes of Anticancer Drugs for Driver Mutation Identification eTable 2. List of Codes for ICD-10 and Medical Procedures eTable 3. Characteristics of Patients With NSCLC Categorized According to Therapy Types eTable 4. Characteristics of Patients With NSCLC Categorized According to Age eTable 5. Characteristics of Patients With NSCLC Categorized According to Sex eTable 6. Characteristics of Patients With NSCLC Categorized According to Details on Therapy Types eTable 7. Characteristics of NSCLC Patients With and Without BMI Values eFigure 1. Distribution of BMI eFigure 2. Hazard Functions of Mortality for Patients Who Received ICI Therapy or Conventional Chemotherapy and Difference of Hazard of Mortality Plotted Against BMI in Sensitivity Analyses eFigure 3. Hazard of Mortality as a Function of BMI Stratified Based on Details on Therapy Types This Supplementary material has been provided by the authors to give readers additional information about their work.eMethods 1. Definitions of patients with NSCLC who received first-line therapy To identify patients who received first-line therapy after lung cancer diagnosis, we included those with a minimum 1-month interval from database entry to the date of first lung cancer diagnosis.In our study, the initiation of chemotherapy after the diagnosis of lung cancer was recorded as the index date.

eMethods 4 .
Detailed information on each analysisMain analysis of Classification by the first-line therapyMethod which is labled as "Classification by the first-line therapy" analyzed patients' data for the entire follow-up period according to their first choice of ICI therapy or conventional chemotherapy after the index date ignoring mid-course switching their therapy.
Abbreviations: ICI, Immune checkpoint inhibitor; BMI, body mass index Abbreviations: BMI, body mass index; ICI, Immune checkpoint inhibitors Hazard functions of mortality for patients who received ICI therapy or conventional chemotherapy and difference of hazard of mortality plotted against BMI in sensitivity analyses © 2024 Ihara Y et al.JAMA Network Open.